IN ILRN. \ I ION \ I Jot RN\I.Or LI PROSY^

Volume 46, Number 2Printed in the U.S.A.

CORRESPONDENCE

phis department is for the publication of inlOrmal communications that are ofinterest because they are informative and stimulating, and for the discussion ofcontroversial matters. "flue mandate of this JotRNAL is to disseminate informationrelating to leprosy in particular and also other m•cobacterial diseases. Dissidentcomment or interpretation on published research is of course valid but personalityattacks on individuals would seem unnecessary. Political comments, valid or not,also are unwelcome. 'hey might result in interference with the distribution of theJOURNAL and thus interfere with its prime purpose.

Ir Genes and Leprosy

To The Editor:

The evidence for genetic factors influenc-ing susceptibility to leprosy needs to be ex-amined more critically than was done by Dr.Hastings in his editorial "Transfer Factor asa Probe of the Immune Defect in Leproma-tous Leprosy" (1,1L 45 [1977] 281-291). Dr.11Iastings has adopted a new name ("the lep-rosy Ir gene hypothesis") for the old theorythat lepromatous leprosy patients have a ge-netically-determined inability to mount acell-mediated immune response to M. lepraeinfection. At present, the new name addslittle to the theory, except perhaps respect-ability, since Ir genes have been defined inrelation to immune responses to syntheticpolypeptides in inbred strains of animals ( 3 ),but not yet in relation to disease suscepti-bility in man ( 9, ' 8 ).'

More than 40 years ago Rotberg ( 16 ) pos-tulated a genetic factor (the N factor) pos-sessed by normal individuals which enabledthem to acquire strong Mitsuda reactivityupon natural exposure to M. leprae or in re-sponse to repeated lepromin testing. He sug-gested that persistently negative individualswho were susceptible to lepromatous leprosylacked the "N factor." Then in the early1960's Beiguelman ( 1 ) obtained data indicat-ing that a negative Mitsuda reaction wassomewhat more frequent among childrenwhose parents were born negative. He sug-gested that the basis for this observation wasa lyser or nonlyser macrophage, the nonlyser

' An exception to this statement may be the case ofsusceptibility to ragweed pollen allergy which seems tobe under H LA-linked Ir gene control ( 13 ).

phenotype being inherited as a recessivetrait ( 2 ). 2 With advances in our understanding of the mechanism of cell-mediated im-munity, the "genetic defect" theory has beenput into more refined terms. The focus hasnow shifted to the T lymphocyte and the hy-pothesis has been advanced by Godal et a!.( 10 ) that a defective immune response (Ir)gene may be the basis for the defective Tcell function.

What is the evidence for the leprosy Irgene hypothesis'? Transfer factor could be auseful probe of the immune defect in lepro-matous leprosy were its mechanism of ac-tion known. However, as it is not, the factthat transfer factor is effective in the treat-ment of lepromatous leprosy tells us next tonothing about the nature of the immune de-fect. Other evidence in favor of the Ir genehypothesis is equally tenuous. Current the-ory requires than an Ir gene should be linkedto the HLA complex. Yet, as Dr. Hastingsnotes, there are no convincing associations .

of leprosy susceptibility with HLA antigens.Promising results were recently obtainedfrom family studies which suggested thatHLA-linked genes control the host responseto M. leprae ( 7 ). However, while furtherstudies by the same group ( 6 ) have con-firmed this finding for tuberculoid leprosy,an association of lepromatous leprosy withHLA could not be confirmed.

2 It must be cautioned in interpreting such data thatMitsuda reactivity is acquired by the majority of thepopulation in an endemic area between the ages of 5and 15 years ( " ). Therefore, if comparisons betweengroups of children are to be valid, the groups must becarefully age-matched.

217

218^ International Journal of Leprosy^ 1978

Although there is little, if any, evidenceavailable to support the leprosy Ir gene hy-pothesis, there is now substantial evidenceagainst it:

First, it has now been shown by histologi-cal methods that about 80% of the patientsoriginally classified as polar lepromatoushave actually passed through a borderlinephase ( 14,15 ). These patients comprise theindefinite or subpolar lepromatous group. Itis clear then that the large majority of lepro-matous patients do have the genetic capacityto mount a cell-mediated reaction to M. lep-rae. Apparently, this reactivity develops toolate and is subsequently overwhelmed by theprogressive infection. The Ir gene hypothesisis not even required to explain the other 20%of lepromatous patients. A slightly longerdelay in the cell-mediated reaction would ex-plain it equally well.

Second, twin studies probably provide thebest evidence for some type of genetic influ-ence in leprosy susceptibility. Yet, at thesame time, they seem to rule out the geneticdefect theory. In the most thorough study( 4 ), 37 of 62 pairs of monozygotic twins werefound to be concordant for leprosy. How-ever, at least 4, and possibly 5 of these 37were discordant for leprosy type, i.e., one ofthe twins had lepromatous leprosy and theother one had tuberculoid leprosy. Again, itis evident that individuals who must havethe genetic capacity to respond to M. lepraeinfection with cell-mediated immunity havenevertheless developed the lepromatousform of the disease.

Third, very recently studies in this Insti-tute have tested directly the hypothesis thatunresponsiveness to Al. leprae is geneticallydetermined ( 20 ). This was done by measur-ing the responses to M. leprae in the lym-phocyte transformation test (LTT) of normalsiblings of polar, indefinite, and borderlinelepromatous patients, and at the same timedetermining the relationship of the normaland lepromatous sibling within the HLA re-gion by the mixed lymphocyte reaction(MLR). We have found that the large majori-ty of normal siblings, in contrast to the lepro-matous group, respond positively to M. lep-rae. Furthermore, those normal siblings whowere HLA-identical to the lepromatous pa-tient responded as well as the H LA-non-identical ones. We have concluded that thespecific T cell unresponsiveness characteris-

tic of lepromatous leprosy is not geneticallydetermined.

It nevertheless seems probable that a ge-netic influence on leprosy susceptibility doesexist, but that, as in the case of tuberculosissusceptibility, it has a complex multifactorialbasis. In fact, the magnitude of the concor-dance for leprosy in monozygotic and dizy-gotic twins is very similar to that found fortuberculosis concordance in twin studies oftuberculosis susceptibility ( 14 ). It is alsoworth noting that tuberculosis shows a spec-trum of disease analogous to that of leprosy( 12 ), and that transfer factor has also beenuseful in treating progressive drug-resistanttuberculosis ( 17 ). Yet, to my knowledge, noone has seriously proposed a "tuberculosis 1rgene."

While a degree of genetic influence seemsprobable, some of the evidence frequentlycited as indicating the existence of geneticfactors in leprosy susceptibility may not beevidence at all:

I. Fan nili clustering of leprosy cases. Thisobservation misled Danielssen and Boeck( 5 ) who erroneously concluded that leprosywas a hereditary disease. It is still possiblethat we may be misled by this observation. Itcould he explained as well by the intensityand/or duration of the exposure to M. lepraeas by the genetic defect theory.

2. Differing patterns of leprosy in differentethnic groups inhabiting the same area.These observations need not he due to gene-tic factors unless all environmental factorsare equivalent. Do the two groups have simi-lar social habits and nutritional levels? Dothey have comparable socio-economic sta-tus? Do they have similar incidences ofother diseases in each age group? It wouldseem to be quite difficult at present to sortout these environmental factors from what-ever genetically-influenced difference in sus-ceptibility to different types of leprosy mayexist in different ethnic groups. It must alsobe remembered that such genetically-deter-mined influences as do exist may operate atquite a different level than by direct controlof the cell-mediated immune response to M.leprae.

3. The specificity of the defect. This factdoes not imply a genetically-determined un-responsiveness, and can be explained by adesensitization theory. Lepromatous patientsseem to be unresponsive to all antigens of

46, 2^ Correspondence^ 219

M. leprae which are capable of evoking acell-mediated response, not just one antigen(or determinant) as might be predicted bythe 1r gene hypothesis. this total unrespon-siveness can be explained by a desensitiza-tion to all Al. leprae antigens, such as may hecaused by the antigen overload associatedwith the massive infection.

4. The persistence of the clef ect. This factdoes not constitute evidence for a geneticetiology of the immune defect because ba-cilli are now known to persist indefinitely inthe body. The permanence of the defect mayalso be a reflection of the profound effects ofa mycobacterial infection which encompass-es the entire reticuloendothelial system, in-cluding the hone marrow ( 19 ).

5. The pre-existence of the clefc ,ct. The pre-existent unresponsiveness is indicated by thedata of Dharmendra and Chatterjee (').However, the lepromin negativity of thoseindividuals destined to develop lepromatousleprosy is equally well explained by a) lackof exposure, b) "inappropriate" exposure(i.e., underexposure, overexposure, or expo-sure by the wrong route), or c) immunosup-pression during the time of exposure (e.g.,by malnutrition, intercurrent infection, preg-nancy, etc.) as by a genetically-determinedunresponsiveness. That the pre-existence ofthe defect has been given so much weight infavor of a genetic etiology may be due tothe fact that the unwarranted assumption ismade that the pre-existent unresponsivenessand the persistent post-infectious unrespon-siveness have the same basis. In fact, theymay have quite different causes, neither oneof them being genetically determined. Thepre-existent unresponsiveness may resultfrom the conditions listed above. The per-sistent post-infectious unresponsiveness, incontrast, is most likely due to the ravages ofthe infection itself. As has been noted, in ap-proximately 80% of lepromatous cases thereis proof of a period of responsiveness be-tween two different periods of unresponsive-ness, i.e., the transient borderline phase ofindefinite lepromatous leprosy.

In view of the paucity of evidence current-ly available to support the leprosy Ir genehypothesis, Dr. Hastings' tentative conclu-sion that, "there is little hope in attemptingimmunization of prelepromatous individualswith Al. leprae" is certainly premature. Itwould seem at present that his alternative

hypothesis which postulates that in someway control mechanisms have gone awry inlepromatous patients may provide a moreplausible etiology for the immune defect oflepromatous leprosy.

—Gerald L. Stoner, Ph. D

Armauer Hansen Research InstituteP.O. Box 1005Addis Ababa, Ethiopia

REFERENCES

I. BEIGUELNIAN B. ilereditariedade de reacdo deMitsuda. Rev. Brasil. Leprol. 30 (1962) 153-172.

2. BLIGUELMAN, 13. The genetics of resistance toleprosy. Int. J. Lepr. 33 (1965) 808-812.

3. BENACERRAF, 13. and KATZ, D. H. The natureand function of histocompatihility-linked im-mune response genes. In: Immunogeneticsand Immunodeficiency, 13. Benacerraf, ed.,Lancaster, England: MTP, 1975, pp 117-177.

4. ClIAKRAVARTTI, M. R. and Vogel, F. A TwinSnub on Leprosy, Stuttgart, Georg Thieme,1973.

5. DANIFLSSEN, D. C. and BoEcK, W. Traits' deSpedalskhed, Paris: Bailliere, 1848.

6. Di. VRIES, R. R. P., FAT, L. , MEIIRA, N. K.,VAIDYA, M. C. and VAN ROOD, J. J. HLA-linked control of susceptibility to tuberculoidleprosy. In: Symposium on Recent Progressin the Immunology of Leprosy, New Delhi:Arnold-Heinemann (in press).

7. DE ViziEs, R. R. P., FAT, L., NLIENIIUIS, L. E.and VAN ROOD 1 I 111.A-finked genetic con-trol of the host response to Al. leprae. Lancet2 (1976) 1328-1330.

8. DuARNIENDRA and CHATTERJLE, K. R. Prog-nostic value of the lepromin test in contacts ofleprosy cases. Lepr. India 27 (1955) 149-158.Reprinted in III. 24 (1956) 315-318 with ad-dendum pp 473-474.

9. DuPoNT, B., HANSEN, J. A. and YUNIS, E. J.Human mixed-lymphocyte culture reaction:genetics, specificity and biological implica-tions. In: Advances in Immunology, NewYork: Academic Press, vol. 23, 1976, pp 107-202.

10. GoDAL, T., MYRVANG, B., FROLAND, S. S.,SIIAO, J. and MELAKU, G. Evidence that themechanism of immunological tolerance("central failure") is operative in the lack ofhost resistance in lepromatous leprosy.Scand. J. lmmunol. 1(1972) 311-321.

11. GuiNTo, R. S., J. A. and MABALAY,E. B. The Mitsuda reaction in persons withand without household exposure to leprosy.Int. J. Lepr. 23 (1955) 135-138.

12. LENZINI, L., Rofroii, P. and Rorrou, L. Thespectrum of human tuberculosis. Clin. Exp.

220^ International Journal of Leprosy^ 1978

Immunol. 27 (1977) 230-237.13. 1,TY1NE, ft ft, STENutER, R. II. and Forixo, M.

Ragweed hay fever: genetic control and link-age to 111,-A haplotypes. Science 178 (1972)1201-1203.

14. RIDLEY, D. S. and .1oPTING, W. 11. Classifica-tion of 1 ,:prosy according to immunity. Int. .I.Lepr. 34 (1966) 255-273.

15. RIDLEY, D. S. and WATERS, M. F. R. Signifi-cance of variations within the lepromatousgroup. Lepr. Rev. 40 (1969) 143-152.

16. RoTnito, A. Some aspects of immunity in lep-rosy and their importance in epidemiology,pathogenesis and classification of forms ofthe disease. Rev. Brasil. Leprol. 5 (1937) 45-97.

17. RUBINSTEIN, A., METANITD, .1. and RopEscu,D. Transfer factor treatment in a patient with

progressive tuberculosis. Clin. Immunol. Im-munopathol. 8 (1977) 39-50.

18. Rvp[R, I,. P. and SVE.IGIARD, A. Ilistocom-patibility associated diseases. In: 13 and TCells in Immune Recognition, F. Loor andG. E. Roelants, eds., London: Wiley, 1977, pp437-456.

19. SHEPARD, C. C. and KARAT, A.13. A. Infec-tivity of leprosy bacilli from hone marrow andliver in patients with lepromatous leprosy.Lepr. Rev. 43 (1972) 21-26.

20. SToNTR, G. F. and 1(11W.w, .I. Lymphocyte re-sponses to M. leprae in normal siblings of lep-romatous patients: influence of 111.A-D iden-tity. hr: Symposium on Recent Progress inthe Immunology of Leprosy, New Delhi: Ar-nold-11 einetnann ( in press).

Transfer Factor as a Probe in the Immune Defectin Lepromatous Leprosy

TO Ttn: Enrro►t:

Thank you for allowing me to respond tothe letter of Dr. Gerald L. Stoner of 9 March1978, regarding the above editorial. In anarea as complex and controversial as the na-ture of the fundamental defect in leproma-tous leprosy, one hardly expects a consensusand Dr. Stoner's comments are most appro-priate in expressing alternate views.

One can only agree with Dr. Stoner's de-sire for more critical evidence hearing on ge-netic factors influencing susceptibility to lep-rosy. The editorial in question was certainlynot intended to he interpreted as an attemptto present any original concepts regardingthis time-honored view. Indeed in references30 and 31 of the editorial, Dr. Rotberg's hy-pothesis is reviewed at some length: Dr.Beiguelman's work is reviewed in reference33; and that of Dr. Godal et al, in reference15 of the editorial.

Obviously this writer strongly disagreeswith Dr. Stoner's statements that imply thatnothing is known about the mechanism ofaction of transfer factor and hence its activ-ity in lepromatous leprosy "tells us next tonothing about the nature of the immune de-fect." As referenced in the editorial, thiswriter feels there is adequate evidence to al-low one to believe that transfer factor actsspecifically and in the fashion indicated. Ifso, in light of the other possibilities for the

fundamental defect in lepromatous leprosy,the results with transfer factor in leprosy ap-pear relevant to this writer's judgment.

Dr. Stoner apparently prefers a very nar-row definition of an Ir gene to mean onlythose defined in inbred strains of animalsstudied by their responses to synthetic poly-peptides. As indicated and referenced in theeditorial (references 38 and 39), this writeris comfortable with a perhaps more impre-cise use of the term to refer to the more than30 Ir genes identified in animals and thequite large number of known associationsbetween diseases and lILA antigens in hu-mans. To he sure, there are alternate expla-nations for these I-ILA-disease associationsin humans, but, in this writer's mind, the evi-dence that these associations are likely to beon the basis of Ir genes appears persuasiveat the moment. The interested reader maywish to read Dupont et al (1976), for a re-view of the evidence on this point.

Dupont, 13., Hansen, J. A. and Whitsett,C. Association between I-ILA and diseases.In: Clinical Evaluation of Immune Func-.tion in Man, Litwin, S. D., Christian,C. L., and Siskind, G. W., eds., New York:Grune & Stratton, 1976, pp 97-132.As to the evidence presented against the

leprosy Ir gene hypothesis, this writer pre-fers to think of indefinite or subpolar lepro-matous leprosy patients as being fundamen-